April 16, 2015

This photograph shows part of the two-dimensional infrared spectroscopy instrument operating in the laboratory of Prof. Andrei Tokmakoff. The normally invisible infrared laser beam appears red in this image with the aid of dry ice. Photo by Robert Kozloff

A newly developed spectroscopy method is helping to clarify the poorly understood molecular process by which an anti-HIV drug induces lethal mutations in the virus’ genetic material. The findings from the University of Chicago and the Massachusetts Institute of Technology could bolster efforts to develop the next generation of anti-viral treatments.

Viruses can mutate rapidly in order to adapt to environmental pressure. This feature also helps them become resistant to anti-viral drugs. But scientists have developed therapeutic anti-viral agents for HIV, hepatitis C and influenza using a strategy called lethal mutagenesis.

This strategy seeks to extinguish viruses by forcing their already high mutation rates above an intolerable threshold. If viruses experience too many mutations, they can’t properly manage their genetic material.

“They can’t replicate and so are quickly eliminated,” said Andrei Tokmakoff, the Henry G. Gale Distinguished Service Professor in Chemistry at UChicago. “In order to make this work, you need a stealth mutagen. You need something sneaky, something that the virus isn’t going to recognize as a problem.”

Tokmakoff and his associates at UChicago and MIT reported new details of the stealthy workings of the anti-HIV agent KP1212 in March in the Proceedings of the National Academy of Sciences. Supporting data were collected with two-dimensional infrared spectroscopy, an advanced laser technique that combines ultrafast time resolution with high sensitivity to chemical structure.

Critical tools

“Two-dimensional infrared spectroscopy will be critical on the path ahead. It lets us look at the structures that exist in aqueous solution, which is the natural milieu of cells,” said study co-author John Essigmann, MIT’s William and Betsy Leitch Professor of Chemistry, Toxicology and Biological Engineering. Essigmann is co-founder of a pharmaceutical company that is developing mutagenic inhibitors of HIV.

“We also have done nuclear magnetic resonance, which is very informative, but those studies were done in organic solvents that probably do not as accurately provide a view of what happens in cells as did the infrared studies done by the Tokmakoff group,” Essigmann said.

Scientists design lethally mutagenic molecules such as KP1212 to resemble natural DNA bases, the adenine-thymine, cytosine-guanine base pairs. “These analogs can bind to the wrong base partners and therefore lead to genetic mutations,” said the study’s lead author, Sam Peng, who was a visiting graduate research assistant at UChicago.

KP1212 is a cytosine variation, which normally would pair with guanine during replication. But biochemical experiments and clinical trials have shown that KP1212 induces mutations by pairing with adenine. A leading proposal suggested that KP1212 derived its mutagenicity by shape shifting—converting into a different molecular structure by repositioning its hydrogen atoms on nitrogen and oxygen atoms.

Scientists call this shape-shifted structure a tautomer. James Watson, SB’47, and Francis Crick proposed this tautomer hypothesis in 1953 when they announced the discovery of DNA’s double-helical structure. “The shuffled hydrogen positions in rare tautomers alter the hydrogen bonding patterns, resulting in incorrect base paring,” said Peng, who completed his doctorate at MIT in 2014 and will become a postdoctoral scientist at Stanford University later this year.

Rapid measurement

Most experimental tools would have difficulty distinguishing between the normal and shape-shifted structures because they interconvert very rapidly. With two-dimensional infrared spectroscopy, the UChicago team was able to distinguish between the two structures. The team also was able to measure how rapidly the shape shifting occurs under physiological conditions: in 20 billionths of a second.

The research team expected to find only two dominant tautomers, but their experiments showed that many more exist. In addition to taking on different forms as a neutral molecule, KP1212 also could accept an extra proton, giving it a positive charge at physiological levels of acidity—pH of approximately five and a half to seven—that made possible even more rearrangements and tautomer structures. “The number of possibilities exploded,” Tokmakoff said.

The experiments also showed that both the protonated and non-protonated forms facilitated the viral mutation rate. Even in the absence of the protonated form, the virus still mutated, just at a lower rate.

“We found that under physiological pHs, KP1212 is significantly protonated and this protonated form induces even higher mutation rates, reaching approximately 50 percent,” Peng said.

The finding that the molecule could become protonated both surprised and delighted Essigmann. The work taught his team how to create even more potent shape shifters—by decorating the KP1212 scaffold with groups of atoms and molecules that further raises their ability to capture protons.

“KP1212 is about 20 percent of the way toward being an ideal therapeutic mutagen. The hints given to us by the spectroscopy guide us toward even better mutagenic molecules,” Essigmann said.

Although Essigmann and Tokmakoff have known each other for years, they pursued seemingly far-removed research specialties until now. Tokmakoff’s biological research involves proteins, not DNA. But together their research teams were able to fruitfully undertake one of the first two-dimensional infrared spectroscopic studies of the therapeutic mechanism of an anti-viral drug.

“This is how basic research works,” Tokmakoff said. “This is how so often you get transitions from basic research to real applications. They can’t be predicted.”

On 26 April 2015, the International Liver Conference, also referred to as EASL, will be convening for its 50th year in Vienna. This year, the organizers offered a new abstract category named “Clinical Trials in Progress”, which gives investigators the opportunity to present information on their ongoing liver research without trial results. The category provides visibility for clinical studies while removing the time consuming process of data analysis typically required for a conference abstract. In light of the milestone conference and this new category, I took a look at the current state of ongoing HCV Phase I-III research conducted by industry sponsors.

As of 13 April 2015, 152 industry trials were ongoing in Trialtrove®.[1] Only 5 evaluate HCV vaccines (data not shown), so I limited this review to the 147 antiviral trials. The majority of ongoing antiviral studies are still recruiting (84/147 trials) and none currently have a status of temporarily closed. Early stage development is limited since only 14% are either Phase I or I/II. Phase II is most common and primarily consists of recruiting trials (Figure 1).

95% of trials involve HCV patients (140/147 trials) rather than healthy volunteers. Patient studies primarily include subjects with HCV genotype 1 (103 trials), which is the most prevalent genotype worldwide[2]. Genotype 1 patients also have the most treatment options for the current wave of direct acting antivirals (DAAs), so it is reassuring to see that a range of target genotypes are also included in Phase II-III trials. A large portion of genotype 1 trials also enroll other genotypes (44/103 trials) and an additional 19 include non-genotype 1 HCV alone (data not shown).

Among the top 5 sponsors, Gilead and Merck are the most active with 33 and 30 studies respectively. Gilead’s ongoing research mostly consists of Phase II trials (20 Phase II and 11 Phase III trials), while Merck’s primary focus is split between Phase II and III (11 trials each). Merck also has the largest number of early stage clinical research among the top 5, but not by much since Phase I and I/II trials are limited across the board. AbbVie’s activity mostly consists of Phase III (12/21 trials), which is double the number of their Phase II trials. The clinical activity for both Johnson & Johnson (J&J) and Bristol-Myers Squibb (BMS) is nearly balanced between Phase II and III. J&J has 8 and 6 ongoing Phase II and III studies, while BMS has 7 and 9 (Figure 2).

Since Gilead is the most active sponsor, it follows that one of their drugs also tops the list of most commonly evaluated compounds. However, it’s interesting that the already approved sofosbuvir (SOF) is evaluated in 44 ongoing trials (Figure 3) while Gilead is only involved in 33 (Figure 2). SOF, which is already quite successful as the approved Sovaldi®, continues to undergo evaluation with other compounds from Gilead as well as in combination with drugs from other sponsors. Most SOF trials are Gilead sponsored and evaluate the drug as a fixed dose combination (FDC) with ledipasvir as the already approved combination known as Harvoni® or with the yet unnamed GS-5816. Some examples where SOF is co-administered with drugs from other sponsors include Merck’s studies with their FDC of elbasvir + grazoprevir and BMS’ with their FDC of asunaprevir + daclatasvir + beclabuvir (data not shown).

FDCs continue to be of high interest for various reasons. They minimize the pill burden for patients to help increase adherence and in turn, improves drug efficacy. They also ensure that drugs with different mechanisms of action are taken in combination, which reduces development of treatment resistance. Drugs from Gilead and AbbVie were most likely to be evaluated as FDC components, especially GS-5816 which is only being evaluated as a FDC. Merck and BMS compounds are currently evaluated as FDC components for 21-53% of their studies while J&J’s simeprevir (Olysio®) is the only one not included in any FDCs. In all trials, the already approved Olysio® continues to be evaluated in combinations with other DAAs as a standalone drug (Figure 3).

Activity doesn’t appear to be slowing down for HCV research and with high activity in later stage trials, additional treatment options will likely become available to various genotype subsets of HCV patients in the near future. It’ll be interesting to see all the results coming out from the upcoming EASL and continue to watch this exciting space of antiviral research.

Methods A systematic literature search was performed to identify studies that assessed the association between SVR and cirrhosis regression. The main outcome studied was cirrhosis regression in patients with a SVR as compared with patients without a SVR. Six studies totalling 443 patients were included. Dichotomous outcomes were reported as risk ratios (RR) with 95% confidence intervals (CI).

Results Of the 443 patients with cirrhosis, 137 achieved a SVR. Of these 137 patients who achieved an SVR, 73 (53%) patients had regression of cirrhosis. The risk ratio of cirrhosis regression was 2.69 [Confidence Interval (CI) 1.45–4.97, P < 0.01] in patients who achieved a SVR. The risk of cirrhosis regression was consistently in favour of patients who achieved a SVR regardless of the length of the biopsy or whether the biopsy was reviewed by a single or multiple pathologists. The risk ratio of cirrhosis regression was related to the duration of follow-up between biopsies. The relative risk for regression of cirrhosis in studies in which the mean or median time for the follow-up liver biopsy was greater than 36-month was 4.33 (CI 1.1–17.0, P = 0.04) as compared to a relative risk of 1.79 (CI 1.26–2.29, P < 0.01) in studies with a mean or median time between the follow-up biopsy of less than 36-month.

Conclusions Our results suggest that the majority of patients with cirrhosis who achieve a SVR develop cirrhosis regression. Time between biopsies appears to be an important determinant of the likelihood of cirrhosis regression.

Introduction

Hepatitis C is one of the leading causes of cirrhosis in the United States.[1] Estimates of the number of Americans infected with hepatitis C range from 3 to 7 million people.[2,3] The public burden is increasingly realized as the percentage of patients with hepatitis C today with cirrhosis is between 15% and 20%.[4] Patients with cirrhosis are at risk of liver failure and hepatocellular carcinoma. Indeed, HCV is currently the most common indication for transplantation in the United States.[5]

The end point of successful antiviral therapy is achieving Sustained Virological Response (SVR).[6] Sustained virological response has been associated with arrest of disease progression; and improvements in quality of life and reduction of liver-related complications and hepatocellular carcinoma risk.[7–9] A number of studies have also documented improvement in liver histology after sustained virological response.[10–17] Histological improvement has been noted even in the context of cirrhosis.[14] While a large meta-analysis has previously demonstrated reduction of cirrhosis-related complications in patients achieving SVR,[18] no previous meta-analysis has examined the likelihood of cirrhosis regression in patients who achieved a SVR.

Cirrhosis has been regarded as the final common pathway of liver disease.[19] Multiple studies have successfully challenged the premise that cirrhosis is irreversible particularly when the liver disease culprit is eliminated.[20–23] In this meta-analysis, we sought to better understand the relationship between SVR and cirrhosis regression in patients with HCV treated with antiviral therapy.

Methods

Objective

To perform a systematic review of the literature and meta-analysis to determine whether cirrhosis is reversible in hepatitis C patients with sustained virological response to antiviral therapy.

Selection of Studies

Trials that met the following criteria were included: (a) prospective or retrospective cohort studies as well as randomized, controlled, open or blinded trials pertinent to the subject matter and published as an article or abstract, (b) studies that reported follow-up data on patients greater than or equal to 6 months, (c) studies including subjects with serological confirmation of chronic HCV infection, (d) SVR defined as no detectable levels of HCV RNA by PCR at least 24 weeks after antiviral treatment, (e) studies that included paired liver biopsies and data regarding histological preparation of biopsies, such as biopsy length, time between biopsies, presence of central pathologist and a validated method of staging cirrhosis, (f) studies that included at least 10 patients. Articles excluded were (a) studies looking specifically at causes of cirrhosis other than Hepatitis C, including Wilson's disease, PSC, PBC, haemochromatosis, alpha-1 antitrypsin and alcoholic cirrhosis, (b) studies including patients with immunosuppression secondary to chronic steroid use, HIV, or any other aetiology, (c) studies in which data could not be extracted for a subset of cirrhotic patients with and without SVR.

Search Strategy

A comprehensive search of the MEDLINE database and the Cochrane Database of Systematic Reviews was performed to find studies published in the English language up to October 2013 that investigated cirrhosis regression in Hepatitis C end-stage liver patients treated with antiviral therapy. We used combinations of the keywords Hepatitis C, antiviral agents, liver cirrhosis, SVR, viral suppression, histology,revers*, regression and improvement. We also manually searched manuscript references to identify additional studies that may have been missed with a MEDLINE-assisted strategy. Medical science liaisons for the appropriate antiviral therapies were contacted to assess for additional studies to review.

Data Extraction

Studies were subjected to inclusion and exclusion criteria. Two reviewers (EA and VM) independently and in duplicate assessed the eligibility and quality of trials. A formal scoring system to rate the study quality of each individual study was not used. Reviewers noted patient liver biopsy length, duration between biopsies, fibrosis scoring system, baseline biopsy score, antiviral therapy, length of treatment and regression of cirrhosis. Three of the six studies examined cohorts of patients with any amount of liver fibrosis on histology.[26–28] In these studies, only data regarding cirrhotic patients were extracted from the text. Efforts were made to contact the authors for demographic and clinical characteristics of cirrhotic patients. Collaboration was established with one author. Regression of fibrosis was defined individually for each scoring modality and is noted in the results section below.

Statistical Analysis

We used the statistical package RevMan (Review Manager, Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration,v2012). RevMan software was developed by the Cochrane Collaboration to facilitate development of systematic reviews and meta-analyses. The Mantel–Haenszel procedure for binary data was used to determine clinical significance of effect. Sensitivity analysis was two-tailed and set at P ≤ 0.05. A random-effects model was employed because of the anticipated variability between trials in terms of patient populations, interventions and concomitant interventions. Heterogeneity between trials was assessed by the chi-squared test with significance set at P ≤ 0.10. The approximate proportion of total variability in point estimates attributed to heterogeneity was calculated by use of the I2 statistic.[25]

Results

Number of Studies

A total of 172 relevant articles were identified using the search criteria detailed above. Twenty-one manuscripts were reviewed in full. After applying the inclusion criteria, six studies[12,14,24,26–28] were used in the final analysis (Fig. 1). The six studies included a total of 443 cirrhotic patients. The median number of patients across each study was 62.5 (range 15–153).[12,14,24,26–28]

Cirrhosis was diagnosed by liver biopsy in all studies. Biopsies were evaluated by Metavir score in five studies.[12,14,24,27,28] The remaining study used the Ishak scoring method to evaluate cirrhosis. A Metavir score of F4 or an Ishak fibrosis score of ≥5 was used to define cirrhosis. All studies reported results for paired biopsies. One biopsy was taken prior to antiviral therapy and one biopsy was taken after antiviral therapy. Biopsy length was reported in five of the six studies.[12,14,24,26,27] The time between each biopsy was listed for all studies (Table 1). A central pathologist was used for diagnosis in two of the six studies.[26,27] These data were not reported in one study.[14] The remaining studies used 2–3 independent reviewers.[24,27,28]

Antiviral Therapy

All studies used interferon-based regimens. Five of the six studies treated patients using interferon or pegylated interferon with or without the addition of ribavirin.[12,14,24,26,27] In Shiratori et al., patients were treated solely with interferon.[28] Duration of therapy across studies varied from 8 to 48 weeks. Specific details regarding antiviral therapy and treatment duration for each study are noted in the table (Table 1). Many of the studies were retrospective analyses of prior randomized controlled trials comparing antiviral dosages and length of therapy (Table 1).[12,14,27,28] The median number of patients achieving sustained virological response across studies was 34% (range 24–44%).[12,14,24,26–28]

Regression of Cirrhosis

Regression of cirrhosis was defined as reduction in Metavir stage to ≤F3 or Ishak fibrosis score to ≤4. Median regression of cirrhosis in patients with SVR across studies was 55% (range 24–83%). Overall, a total of 73 patients with SVR had regression of cirrhosis of a total of 137 patients with SVR (53%). Of note, regression of cirrhosis in patients who did not achieve SVR was also observed. Median regression of cirrhosis in these patients was 19.5% (range 2–44). Risk ratios were calculated to compare regression of cirrhosis in patients with SVR against regression of cirrhosis in patients without SVR. Relative risk for regression of cirrhosis across all studies was 2.69 (95% CI 1.45–4.97, P < 0.01) (Fig. 2).

Figure 2.

Meta-analysis overall result – Cirrhosis regression in patients with and without a sustained viral response.

Subgroup Analysis

A number of subgroup analyses were also performed. The relative risk ratio for studies that studied only cirrhotic or advanced fibrosis patients was 6.15 (95% CI: 3.18–11.91, P < 0.01).[12,14,24] The relative risk ratio for studies utilizing a central pathologist to review liver biopsy slides as compared with studies without a central pathologist was 1.60 (95% CI: 1.20–2.13, P < 0.01)[26,27] and 3.97 (95% CI: 1.51–10.45, P = 0.005)[12,14,24,28] respectively. Studies in which the mean biopsy length or median biopsy length of liver samples was less than 15 mm had a relative risk ratio of 1.91 (95% CI: 1.18–3.09, P = 0.008),[24,26,28] whereas studies that had mean biopsy length or median biopsy length greater than 15 mm had a relative risk ratio of 4.38 (95% CI: 0.95–20.25, P = 0.06)[12,14,27] for regression of cirrhosis. Subgroup analyses were also performed comparing studies in which the mean time between liver biopsies or median time between liver biopsies was less than 36-month or greater than 36-month. The relative risk ratio for cirrhosis regression in these studies was 1.79 (95% CI: 1.26–2.29, P < 0.01) (Fig. 3)[24,26,27] and 4.33 (95% CI: 1.1–17.0, P < 0.05) (Fig. 4)[12,14,28] respectively.

Figure 3.

Follow-up biopsy time mean or median <36-month subgroup analysis – Cirrhosis regression in patients with and without a sustained viral response in trials in which the follow-up biopsy had mean or median time of <36-month.

Figure 4.

Follow-up biopsy time mean or median >36-month subgroup analysis – Cirrhosis regression in patients with and without a sustained viral response in trials in which the follow-up biopsy had a mean or median time of >36-month.

Discussion

Overall, there was considerable variability in the amount of cirrhosis regression across studies (Median 55%, range: 24–83%). When the data were pooled and analysed, we obtained a relative risk of 2.96 indicating that achieving sustained virological response (SVR) led to an almost three-fold increase in chance of cirrhosis regression than not achieving SVR. Half the trials in this analysis studied not just regression of cirrhosis but also improvement in histological score for non-cirrhotics.[26–28] When our analysis was performed only in manuscripts that specifically studied antiviral therapy in patients with severe fibrosis or cirrhosis, a greater likelihood of cirrhosis regression was noted – 6.15.

The severity of liver disease is a well-known predictor of antiviral response, even with newer direct-acting agents.[29] Potentially, regression may be less likely in patients with more advanced or established cirrhosis. Differences in patient selection may help explain the greater likelihood of cirrhosis regression in studies focusing on patients with advanced liver disease. For instance, it is possible that more stringent entry criteria were utilized in studies focused specifically on patients with severe fibrosis or cirrhosis. We were unable to cumulatively analyse steatosis, comorbidities, alcohol among studies to determine their association with cirrhosis regression.

An important finding in our analysis is that the likelihood of cirrhosis regression may increase over time after SVR is achieved. This is highlighted by the fact that the risk ratio for regression is 4.13 when the follow-up biopsy is taken ≥36-month as compared to a risk ratio of 1.79. These results are consistent with studies identifying SVR as a statistically significant predictor of histological response to antiviral therapy.[30,13] Individual studies have demonstrated reduced liver-related morbidity and mortality in patients with advanced hepatic fibrosis or cirrhosis and SVR.[31,32] These results were further supported by a recent meta-analysis demonstrating a significant risk reduction in hepatic decompensation, hepatocellular carcinoma and liver-related mortality in patients with SVR.[18] The histological outcomes observed in this meta-analysis may provide an explanation for the clinical outcomes observed in previous studies.

A noteworthy finding in our analysis is that cirrhosis regression was seen even among treated patients who did not achieve a SVR.[12,14,24,26–28] There are several potential explanations for this. First, the 'Non-SVR' comparative group in our analysis did receive interferon.[12,14,24,26–28] Poynard et al. noted identified factors other than SVR that were associated with decreased fibrosis after treatment, including age <40, lower BMI, and mild or no activity of the virus in a multivariate analysis.[27] In addition, it is possible that other factors promoting cirrhosis such as alcohol consumption may have improved in the 'Non-SVR' group. Indeed, 25% of the patients in the study by Shiratori et al. reported alcohol prior to the study initation.[28] But, the majority of the patients had completely stopped drinking at study completion.

Optimal liver biopsy length has been a subject of intense controversy because of the risk of sampling variation and interpretation.[34] Biopsy sampling variation can limit the interpretation of results. Studies have shown that this sampling variation can lead to ≥1 stage change in fibrosis score when biopsies are taken from different lobes of the liver or even when taken through the same skin puncture site.[35–38] Within our analysis, we found that the cirrhosis regression was better documented when a minimal biopsy length was utilized in the analysis. Although there was a trend, the difference was not statistically significant. To reduce further discrepancies, AASLD has issued a Class IC recommendation that liver biopsy length be at least 2–3 cm.[34] Analysis by an experienced pathologist or consensus reading between pathologists has been associated with increased agreement.[39] Interestingly, studies that used more than one pathologist had a higher regression of cirrhosis benefit as compared with those studies using a central pathologist (RR 3.96 vs. 1.71).

There are a number of limitations to this study. Heterogeneity between studies is an important limitation of this meta-analysis. Possible factors accounting for the heterogeneity may include relatively small study size, antiviral therapy, patient population, prevalence in confounding factors or duration of follow-up. It is not possible to extrapolate our results to patients with decompensated liver disease. All studies limited clinical trial entry to patients with compensated cirrhosis. This may be secondary to the risk of hepatic decompensation and worsening cytopenias with interferon-based therapy. Now with the introduction of non-interferon-based therapy for hepatitis C, the pool of patients with advanced liver disease who are eligible for treatment will expand.[40,41] A third limitation is the utilization of only two literature databases – Cochrane and Medline. We may have missed studies not found in those indices. However, we searched through the references of all identified manuscripts to be as complete as possible. Our results may also be subject to publication bias in that authors were more likely to publish if there was a cirrhosis regression than not.

With the emergence of new therapies and better therapies for hepatitis C upcoming, further study into whether these new therapies may lead to different cirrhosis regression rates must be evaluated.[41] Patients with advanced liver disease are more likely to undergo therapy with non-interferon based therapy. For instance, moderate thrombocytopenia is not necessarily an absolute contraindication with the newer therapies.[40–42] We believe that with the advent of the newer therapies, previously interferon ineligible patients may be candidates for antiviral therapy but the rate of cirrhosis regression remains to be seen when treating patients with more advanced liver disease.

FDA approved changes to the Olysio (simeprevir) package insert to include two new Warnings and Precautions;

serious symptomatic bradycardia when co-administered with sofosbuvir and amiodaron

hepatic decompensation and hepatic failure.

Additional changes to the Indication and Usage, Dosage and Administration, Adverse Reactions, Drug Interactions, Use in Specific Populations and Pharmacokinetic sections of the label were made based on these Warnings and Precautions and are summarized below.

Summary of new WARNINGS AND PRECAUTIONS

5 WARNINGS AND PRECAUTIONS

5.1 Serious Symptomatic Bradycardia When Co-administered with Sofosbuvir and Amiodarone

Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is co administered with sofosbuvir in combination with another HCV direct acting antiviral, including OLYSIO. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir/sofosbuvir). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with co administration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this bradycardia effect is unknown.

Co administration of amiodarone with OLYSIO in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no other alternative treatment options, and who will be co administered OLYSIO and sofosbuvir:

Counsel patients about the risk of serious symptomatic bradycardia

Cardiac monitoring in an in-patient setting for the first 48 hours of co administration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.

Patients who are taking sofosbuvir in combination with OLYSIO who need to start amiodarone therapy due to no other alternative treatment options should undergo similar cardiac monitoring as outlined above.

Due to amiodarone’s long elimination half-life, patients discontinuing amiodarone just prior to starting sofosbuvir in combination with OLYSIO should also undergo similar cardiac monitoring as outlined above.

Hepatic decompensation and hepatic failure, including fatal cases, have been reported postmarketing in patients treated with OLYSIO in combination with peginterferon alfa and ribavirin or in combination with sofosbuvir. Most cases were reported in patients with advanced and/or decompensated cirrhosis who are at increased risk for hepatic decompensation or hepatic failure. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between treatment with OLYSIO and these events has not been established [see Adverse Reactions (6.2)].

OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) [see Dosage and Administration (2.5) and Use in Specific Populations (8.8)].

In clinical trials of OLYSIO, modest increases in bilirubin levels were observed without impacting hepatic function [see Adverse Reactions (6.1)]. Postmarketing cases of hepatic decompensation with markedly elevated bilirubin levels have been reported. Monitor liver chemistry tests before and as clinically indicated during OLYSIO combination therapy. Patients who experience an increase in total bilirubin to greater than 2.5 times the upper limit of normal should be closely monitored:

Patients should be instructed to contact their healthcare provider if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces.

Discontinue OLYSIO if elevation in bilirubin is accompanied by liver transaminase increases or clinical signs and symptoms of hepatic decompensation.

Administer OLYSIO in combination with other antiviral drugs for the treatment of CHC infection. Monitor liver chemistry tests before and during OLYSIO combination therapy [see Warnings and Precautions (5.2)]. OLYSIO monotherapy is not recommended. For specific dosing recommendations for the antiviral drugs used in combination with OLYSIO, refer to their respective prescribing information.

2.5 Hepatic Impairment

OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child Pugh Class B or C) [see Use in Specific Populations (8.8)]. There have been postmarketing reports of hepatic decompensation, hepatic failure, and death in patients with advanced or decompensated cirrhosis receiving OLYSIO combination therapy [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)]. Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) [see Clinical Pharmacology (12.3)].

Elevations in bilirubin were predominately mild to moderate (Grade 1 or 2) in severity, and included elevation of both direct and indirect bilirubin. Elevations in bilirubin occurred early after treatment initiation, peaking by study Week 2, and were rapidly reversible upon cessation of OLYSIO. Bilirubin elevations were generally not associated with elevations in liver transaminases. The frequency of elevated bilirubin was higher in subjects with higher simeprevir exposures.

6.2 Postmarketing Experience

The following adverse reactions have been reported during post approval use of OLYSIO. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship between drug exposure and these adverse reactions.

Cardiac Disorders: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with sofosbuvir in combination with another HCV direct acting antiviral, including OLYSIO [see Warnings and Precautions (5.1) and Drug Interactions (7.3)].

Co‑administration of amiodarone with OLYSIO in combination with sofosbuvir is not recommended because it may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. If co‑administration is required, cardiac monitoring is recommended [see Warnings and Precautions (5.1), Adverse Reactions (6.2)].

­ amiodarone

Caution is warranted and therapeutic drug monitoring of amiodarone, if available, is recommended for concomitant use of amiodarone with an OLYSIO-containing regimen that does not contain sofosbuvir.

Concomitant use of OLYSIO with amiodarone when given orally may result in mild increases in amiodarone concentrations due to intestinal CYP3A4 inhibition by simeprevir.

Refer to the prescribing information for the antiviral drug(s) used in combination with OLYSIO regarding their use in patients with hepatic impairment. The combination of OLYSIO with Peg IFN alfa and RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment).

The safety and efficacy of OLYSIO have not been established in HCV infected patients with moderate or severe hepatic impairment (Child Pugh Class B or C).

OLYSIO is not recommended for use in patients with moderate or severe hepatic impairment (Child Pugh Class B or C) [see Dosage and Administration (2.5), Warnings and Precautions (5.2) and Use in Specific Populations (8.8)].

Based on a population pharmacokinetic analysis of HCV infected subjects with mild hepatic impairment (Child-Pugh Class A) treated with OLYSIO, liver fibrosis stage did not have a clinically relevant effect on the pharmacokinetics of simeprevir.

Refer to the prescribing information for the antiviral drugs used in combination with OLYSIO regarding their use in patients with hepatic impairment.

Drug Interactions

[See also Warnings and Precautions (5.67) and Drug Interactions (7)]

In vitro studies indicated that simeprevir is a substrate and mild inhibitor of CYP3A. Simeprevir does not affect CYP2C9, CYP2C19 or CYP2D6 in vivo. Simeprevir does not induce CYP1A2 or CYP3A4 in vitro. In vivo, simeprevir mildly inhibits the CYP1A2 activity and intestinal CYP3A4 activity, while it does not affect hepatic CYP3A4 activity. Simeprevir is not a clinically relevant inhibitor of cathepsin A enzyme activity.

In vitro, simeprevir is a substrate for P gp, MRP2, BCRP, OATP1B1/3 and OATP2B1; simeprevir inhibits the uptake transporters OATP1B1/3 and NTCP and the efflux transporters P gp/MDR1, MRP2 and BSEP. The inhibitory effects of simeprevir on the bilirubin transporters OATP1B1/3 and MRP2 likely contribute to clinical observations of elevated bilirubin [see Adverse Reactions (6.1)].

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